Translational stress research has aimed to elucidate the biological mechanisms through which psychological stress influences disease pathophysiology in humans. Advancement in this field has been challenged by a technology gap that forces researchers to employ either comprehensive but invasive methods (e.g., genomic profiling after venipuncture) or minimally-invasive but non-comprehensive methods (e.g., salivary assays). AIM. We aim to validate a comprehensive and minimally-invasive method to study stress biology in humans, by testing whether minimally-invasive blood collection methods, namely dried blood spots and capillary blood collection, could be used to detect stress-related changes in genome-wide expression patterns. METHODS. First, for laboratory validation, we will collect RNA from dried blood spots, capillary blood, and venous blood in 10 healthy volunteers. We will then test the reliability, the validity, and the sensitivity of genomic profiles from minimally-invasive specimen-collection procedures. These tests will inform the choice of dried blood spots or capillary blood for specimen collection in a clinical validation. Second, for clinical validation, we will ask a population-representative sample of 1,250 pairs of 16-year-old UK monozygotic twins followed-up by the Twins Early Development Study (TEDS) to complete a computerized version of the Perceived Stress Scale and we will select the 35 most discordant twin pairs on this measure. We will then test whether microarray analysis from minimally-invasive assays can identify gene expression differences in pairs of young individuals with identical DNA sequences but different exposure to stress. IMPLICATIONS. The validation of a minimally-invasive assay to study the genomic fingerprint of stress will provide researchers with the technology needed to perform comprehensive assessment of stress biology in larger, more population-representative, and younger human samples.